This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Earlier, we reported that the co-inhibitory receptor PD-1 is highly expressed by the exhausted virus-specific CD8 T cells during chronic SIV infection and in vitro blockade of PD-1 enhances cytokine production and proliferative capacity of these cells (Velu et. al., J Virol 81:5819-28). Impressively, in vivo blockade of PD-1 using an antibody specific to PD-1 resulted in restoration of anti-viral CD8 and B cell function that was associated with enhanced control of plasma viremia and prolonged survival (Velu et. al., Nature 458:206-10). The PD-1: PD-1 ligand pathway consists of the PD-1 receptor and its two ligands PD-L1 and PD-L2. The PD-1 ligands have distinct patterns of expression. PD-L2 (B7-DC;CD273) is inducibly expressed only on DCs and macrophages, whereas PD-L1 (B7-H1;CD274) is broadly expressed on both professional antigen presenting cells (APC) and nonprofessional-APC. Studies in mice demonstrated that blockade of PD-L1 during chronic LCMV infection can restore the function of anti-viral CD8 T cell response. However, the role of interaction between PD-1 and PD-L2 for T cell exhaustion is not clearly understood. Here, we investigated the expression of PD-L2 on APC and the effects of in vivo blockade of PD-L2 during chronic SIV infection. Our results demonstrated that in vivo blockade of PD-L2 is not as effective as in vivo blockade of PD-1 in restoring function of anti-viral immunity in SIV-infected macaques.